We have demonstrated that the autoantibodies produced by patients with Pemphigus Vulgaris and Fogo Selvagem are pathogenic and are responsible for inducing the disease in humans. This has established the true autoimmune nature of these diseases of obscure etiology. We have selected Fogo Selvagem to investigate the etiology of pemphigus because of its unique epidemiology, i.e., it is endemic in certain regions of Brazil, where there are currently more than 10,000 registered cases. In comparison, pemphigus in North America is very rare. The affected population includes farmers, children and young adults of all ethnic groups. The disease has a striking epidemiology that strongly implicates an infectious "agent", transmitted by an insect vector (a fly of the genus Simulium). We include 3 Specific Aims in this Proposal. (a) The first aim describes the evaluation of the titers of pemphigus autoantibodies in patients and controls from endemic and nonendemic areas in Brazil. (b) The second study will examine the incidence and prevalence of a new autoantibody system discovered in the sera of two patients with Fogo Selvagem (designated as Cascas-42). This autoantibody is highly specific for the 56.5 K murine keratin and decorates the cell surface of keratinocytes, suggesting that it recognizes an extracellular domain of this keratin. (c) The third aim will study "foreign antigens" in the epidermis and sera of patients as well as in extracts made of the insects (Simulium) which are suspected to be vectors of Fogo Selvagem. We believe now that the systematic study of Fogo Selvagem as described in this grant will establish the foundations which may culminate in the identification of the etiological agent of this autoimmune disease. If we accomplish this goal, it would probably represent the first study that establishes an etiology for a human autoimmune disease. Equally important perhaps, these studies may present new concepts in keratin biology. We have evidence that certain keratins may have domains, inserted into the cell membrane (transmembrane?) that are exposed on the keratinocyte surface where they become entangled with similar structures of neighboring cells to form an "exoskeleton" which is located in the epidermal intercellular spaces and linked to the keratinocyte cytoskeleton. This exoskeleton-cytoskeleton framework may provide structural support to the whole epidermis.